The present invention relates to pharmaceuticals, tyrosine kinase inhibitors, ACK1 inhibitors, substituted imidazopyrazines and imidazotriazines, preparation thereof, pharmaceutical formulations and compositions, disease treatment therewith, and cancer treatment.
The activated p21cdc42Hs-associated kinase (ACK1) gene encodes an intracellular, non-receptor tyrosine kinase that binds cdc42Hs in its GTP-bound form and inhibits both the intrinsic and GTPase-activating protein (GAP)-stimulated GTPase activity of p21cdc42, a Ras-like protein involved in cell growth. This binding is mediated by a polypeptide of 47 amino acids C-terminal to an SH3 domain.
The ACK1 gene contains a tyrosine kinase domain and is reported to possess tyrosine kinase activity. ACK1 is activated by multiple extracellular stimuli (e.g., EGF, PDGF, IGF, TGFb, Gas6, ECM, stress, etc.). Upon activation, ACK1 mediates signaling cascade by direct interacting with and phosphorylating downstream effectors via its SH3, CRIB or/and proline-rich domains.
ACK1 kinase activity is regulated in the context of cell attachment and detachment, and certain cancer cells depend on ACK1's kinase activity for adhesion, anchorage independent growth and survival. ACK1 is implicated in cell motility, receptor endocytosis, and enhancement of tumorigenesis/metastasis & tumor cell survival. ACK1 is amplified and overexpressed in primary human tumors. ACK1 is amplified and overexpressed in several types of metastatic tumors and promotes prostate tumorigenesis; and phosphorylates tumor suppressor Wwox. Down regulation of ACK1 kinase activity or ACK1 expression levels can result in reduced tumor growth.
It is desirable to identify effective inhibitors of ACK1 for use in proliferative diseases, such as, but not limited to, cancer. There is a continuing need for new anticancer pharmaceuticals. Various publications refer to imidazopyrazines, triazines, and other compounds as tyrosine kinase inhibitors.
Additional background may be found in Nature 363(6427):364-367 (1993); JBC 274:8524 (1999); Cancer Res 65:10514 (2005); PNAS 102:15901 (2005); PNAS 103:9796 (2006); PNAS 104:8438 (2007); Bioorg. & Med. Chem. Lett. 17:1091-97 (2007); US2003/0175763; US200610019957; US2006/0084654; US2006/0235031; US2007/0112005; US2007/0149521; US2007/0280928; US2008/0014200; US200810076921; US2008/0139582; US 2008/0108636; and WO2007/079164.